CV Risk Reduction, Diabetes Prevention, and TZDs

UKPDS 34: Intensive glucose control andCV protectionn = 1704 overweight, with diabetes; n = 342 metformin group

UKPDS Group. Lancet. 1998;352:854-65.

Favors metforminor intensive

Favors usual care

All-cause mortalityMetforminIntensive

Myocardial infarctionMetforminIntensive

StrokeMetforminIntensive

0.02

0.12

0.08

Aggregate endpoints P*

0 1 2

*Metformin vs other intensive therapy (sulfonylurea or insulin)

Relative risk(95% CI)

DCCT/EDIC: Lower glucose = lower long-term CV risk

DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:2643-53.

Primary outcome: Nonfatal MI, stroke, CV death, confirmed angina, revascularization

Mean follow-up: 6.5 yr (1983–1993)

DCCTType 1 diabetes, ages 13 to 40 yr

N = 1441

EDICn = 1394 (97%)

Follow-up: 11 yr (1994–2005)

Intensive diabetes therapy* Conventional diabetes therapy†

All patients offered intensive treatment

*≥3 insulin injections or pump admin/day†1–2 injections/day

DCCT/EDIC Study Research Group.N Engl J Med. 2005;353:2643-53.

DCCT/EDIC: Intensive glucose control reduces long-term CV risk

42%(95% CI 9%–63%)

P = 0.02

57%(95% CI 12%–79%)

P = 0.02

Cumulative incidence

of any first CV event

CumulativeCV death,

nonfatal MI,stroke

Time (years) Time (years)

Conventional52 events

Intensive31 events

Conventional25 events

Intensive11 events

0

0.12

0.08

0.10

0.06

0.04

0.02

0 5 10 15 20

0

0.12

0.08

0.10

0.06

0.04

0.02

0 5 10 15 20

N = 1441 with type 1 diabetes

DCCT/EDIC: Intensive treatment slows renal changes

DCCT/EDIC Study Research Group.N Engl J Med. 2005;353:2643-53.

Microalbuminuria: albumin excretion rate ≥40 mg/24 hrAlbuminuria: albumin excretion rate ≥300 mg/24 hr*P < 0.01, †P < 0.05 vs intensive treatment

Intensive Conventional

9

2

0

5

10

15

20

Microalbuminuria Albuminuria

Patients (%)

Microal-buminuria

Albumin-uria

6*

17*

57

End

EDIC year 11DCCT

5

13*

Baseline

0 1

End

0

3

†

Baseline

N = 1441 with type 1 diabetes

Vascular effects of thiazolidinediones (TZDs)

Examining the clinical impact of TZDs

TZDs impact carotid IMT

Study (year) TreatmentPatients

(Duration) IMT (mm)

Minamikawa(1998)

TRO 400 mgUsual care

DM2 (6 mo)

0.08, TRO0.03, Usual careP < 0.001

Koshiyama(2001)

PIO 30 mgUsual care

DM2(6 mo)

0.08, PIO0.02, Usual careP < 0.001

Sidhu(2004)

ROSI 8 mgPlacebo

Stable CAD(48 wk)

0.01, ROSI0.03, PlaceboP = 0.03

Langenfeld(2005)

PIO 45 mgGLIM 2.7 mg (mean)

DM2(6 mo)

0.05, PIO0.01, GLIMP < 0.005

Minamikawa J et al. J Clin Endocrinol Metab 1998.Koshiyama H et al. J Clin Endocrinol Metab 2001.

Sidhu JS et al. Arterioscler Thromb Vasc Biol 2004.Langenfeld MR et al. Circulation 2005.

TRO = troglitazonePIO = pioglitazoneROSI = rosiglitazoneGLIM = glimepiride

TZD impact on restenosis in type 2 diabetes

38.240.4

17.6

23.0

0

10

20

30

40

50

Choi D et al. Diabetes Care. 2004;27:2654-60.

*8 mg before catheterization, 4 mg/d thereafter, combined with conventional antidiabetic therapy

Change at 6 months

(%)

P = 0.03 P = 0.004

Restenosis rate at ≥50% stenosis

Stent diameter reduction

ROSI* (n = 38 w/51 lesions)Control (n = 45 w/55 lesions)

N = 95 with DM2 and CAD

Neointimalarea

Neointimalarea

Neointimalarea

Restenosis

-60

-50

-40

-30

-20

-10

0

TRO* TRO PIO ROSI

Reductionover

6 mo (%)

TZDs consistently reduce restenosis after coronary stenting in patients with diabetes

Endpoint

1Takagi T et al. J Am Coll Cardiol 2000. 2Takagi T et al. Am J Cardiol 2002.

3Takagi T et al. Am Heart J 2003. 4Choi D et al. Diabetes Care 2004.

*vs diet†vs other anti-diabetes therapy

†††

P < 0.0001

P < 0.0001

P < 0.0001

P = 0.03

-43

-50

-39

-54

Surrogate outcome results driving major TZD trials

TZDs are associated with reductions in atherosclerotic progression and restenosis

TZDs reduce inflammatory markers (CRP, TNF) independent of glycemic control

Reducing CV risk factors with TZDs may also reduceCV morbidity and mortality

Dormandy JA et al. Lancet. 2005;366:1279-89.

Major TZD outcome trials

2005 2006 2007 2008 2009

PROactiveADOPT

CHICAGO DREAM APPROACH

ACCORDBARI-2DORIGIN

ACT-NOW VADT

PERISCOPERECORD

Major TZD outcome trials

2005 2006 2007 2008 2009

PROactiveADOPT

CHICAGO DREAM APPROACH

ACCORDBARI-2DORIGIN

ACT-NOW VADT

PERISCOPERECORD

Dormandy JA et al. Lancet. 2005;366:1279-89.

PROactive: Study design

Pioglitazone 15 mg qdtitrated to 45 mg qd

Randomized, double-blind controlled trial N = 5238 with type 2 diabetes and macrovascular disease

Primary outcome: Composite of all-cause mortality, MI (including silent MI), ACS, stroke, revascularization, leg amputation

Secondary outcome: All-cause mortality,MI (excluding silent MI), stroke

PROspective pioglitAzone Clinical Trial In macroVascular Events

Mean follow-up: 34.5 months

Placebo

PROactive: CV history at baseline

Dormandy JA et al. Lancet. 2005;366:1279-89.

Pioglitazonen = 2605

Placebon = 2633

MI 47 46

Stroke 19 19

PCI or CABG 31 31

Acute coronary syndromes 14 14

Coronary artery disease 48 48

Peripheral arterial disease 19 20

History of hypertension 75 76

≥2 macrovascular disease criteria 47 49

%

PROactive: CV medications at baseline

Dormandy JA et al. Lancet. 2005;366:1279-89.

Pioglitazonen = 2605

Placebon = 2633

-blockers 55 54

ACEIs 63 63

ARBs 7 7

CCBs 34 37

Nitrates 39 40

Thiazide diuretics 15 16

Antiplatelets 85 83

Aspirin 75 72

Statins 43 43

Fibrates 10 11

%

PROactive: Nonsignificant reduction in primary outcome

Dormandy JA et al. Lancet. 2005;366:1279-89.

Events(%)

All-cause mortality, nonfatal MI,* ACS, stroke, coronary or peripheral revascularization, leg amputation

*Including silent MI

Time from randomization (months)

5

10

15

25

06

20

0 12 18 24 30 36

Pioglitazone514 events

Placebo572 events

10% RRRHR 0.90 (0.80–1.02)

P = 0.095

PROactive: Significant reduction in secondary outcome

Dormandy JA et al. Lancet. 2005;366:1279-89.

Events(%)

*Excluding silent MI

0

60 12 18 24 30 36

Time from randomization (months)

16% RRRHR 0.84 (0.72–0.98)

P = 0.027

5

10

15

25

20

Pioglitazone301 events

Placebo358 events

All-cause mortality, nonfatal MI*, stroke

PROactive: Subgroup analysis–Previous MI

• Pioglitazone reduced risk of CV events, including: Fatal/nonfatal MI* by 28% (P = 0.045)ACS by 37% (P = 0.035)

• Over 3 years, pioglitazone added to medication in 1000 patients could prevent:

22 recurrent MIs23 ACS events

• Future studies are needed to further elucidate the underlying mechanism(s) of these clinical results

Adapted from Erdmann E. AHA 2005. www.PROactive-results.com.*Excluding silent MI

n = 2445 with previous MI (≥6 mo)

PROactive: HF hospitalization and mortality

Pioglitazonen (%)

Placebon (%) P

HF leading to hospital admission*

Fatal HF

149 (5.7)

25 (0.96)

108 (4.1)

22 (0.84)

0.007

NS

Dormandy JA et al. Lancet. 2005;366:1279-89.*Non-adjudicated

N = 5238

25

20

15

10

5

0

0 1 2 3 4 5

0 1 2 3 4 50

10

20

30

40

PROactive vs landmark clinical trials: Comparative benefit in patients with diabetes

*Nonfatal

CHD death,

MI*, revasc

(%)

Years

Pravastatin

PlaceboCARE

Circulation. 1998;98.

25% RRRP = 0.05

www.proactive-results.com.Lancet. 2000;355.

Lancet. 2003;361.

MI, stroke, CV death

(%)

Vascular events

(%)

Cardiac death,

MI*,coronary revasc,

ACS(%)

Years0 1 2 3

Years

0 1 2 3 4 5 6Years

Ramipril

Placebo

0

30

20

10 Simvastatin

Placebo

0

5

10

20

Pioglitazone

Placebo

HPS

MICRO-HOPE PROactive

22% RRR P < 0.0001

19% RRRP = 0.034

25% RRRP = 0.0004 15

PROactive in perspective

• Significant 16% reduction in secondary outcome(MI, stroke, or death) despite nonsignificant 10% reduction in primary outcome

• HF hospitalizations increased vs placebo, though HF deaths were similar

• TZD effect on plaque stability and inflammation might contribute to CV benefits

• 3-year trial may be too short to definitively evaluate CV treatment effect; event curves did not begin to separate until 18 months

Dormandy JA et al. Lancet. 2005;366:1279-89.Fonseca V et al. J Clin Endocrinol Metab. 2006;91:25-7.

Meisner F et al. Arterioscler Thromb Vasc Biol. 2006;26:845-50.

Fluid retention after TZD use tends to be peripheraln = 99 with diabetes, chronic systolic HF, and fluid retention; 34% NYHA III–IV

Tang WHW et al. J Am Coll Cardiol. 2003;41:1394-8.

Patients(%)

No TZD (n = 80) TZD (n = 19)

63

11

32

0

18

7380

95

0

20

40

60

80

100

Pulmonaryedema

Jugular venousdistention

Ascites Peripheraledema

Managing TZD-related fluid retentionn = 260 with type 2 diabetes

-0.89

-0.70

-0.02

0.24

-0.12

Karalliedde J et al. Diabetes. 2005;54(suppl 1):A20-1.

ROSI ROSI +furosemide

40 mg/d

ROSI + HCTZ

25 mg/d

ROSI +spironolactone

50 mg/d

Placebo(ROSI

discontinued)

Hct = hematocritROSI = rosiglitazone 4 mg bid

0.50

0.25

0

-0.25

-0.50

-0.75

-1.00

Change in Hct

(%)

Collecting duct (CD) PPAR: Potential mechanism for volume expansion

0

20

40

60

80

100

Control CD PPAR KO

32.2%

15.5%

Zhang H et al. Proc Nat Acad Sci. USA. 2005;102:9406-11.

CD-specific PPAR knockout (KO) mouse model vs control

P < 0.001

P = NS

Vehicle Rosiglitazone 320 mg/kg diet

Plasma volume (µL/g body wt)

TZDs associated with lower mortality

Masoudi FA et al. Circulation. 2005;111:583-90.

Follow-up (days)

Proportionof patientssurviving

N = 16,417 Medicare patients with diabetes and HF (1998–1999, 2000–2001)

0.6

0.7

0.8

1.0

050 100 300150 200 250

0.9

0 350

13% RRRHR 0.87 (0.80–0.94)

No insulin sensitizer (n = 12,069)

Thiazolidinedione (n = 2226)

TZDs in type 2 diabetes and HF

Class I–II

• Use cautiously

• Initiate treatment at lowest dose

• Escalate dose gradually

• Allow more time than usual to achieve A1C target

Class III–IV

• TZDs should not be used at this time

Nesto RW et al. Circulation. 2003;108:2941-8.

AHA/ADA consensus statement, NYHA HF classification

Major TZD outcome trials

2005 2006 2007 2008 2009

PROactiveADOPT

CHICAGO DREAM APPROACH

ACCORDBARI-2DORIGIN

ACT-NOW VADT

PERISCOPERECORD

DREAM: Background and study objective

• Previous studies have shown evidence for new-onset diabetes with RAAS and PPAR agonists

• Does treatment with ramipril and/or rosiglitazone prevent or delay the development of diabetes in persons with IGT or IFG and no diabetes?

DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

Diabetes REduction Assessment with ramipril and rosiglitazone Medication

Reduction in new diabetes

(%)

Adapted from Pepine CJ, Cooper-Dehoff RM. J Am Coll Cardiol 2004.Julius S et al. Lancet 2004.

PEACE Trial Investigators. N Engl J Med 2004.

RAAS modulation reduces new-onset diabetesTreatment with ACE inhibitors or ARBs

SCOPE

CHARM

ANBP2

LIFE

HOPE

ALLHAT

CAPPP

STOP-2

VALUE

PEACE

-40

-30

-20

-10

0

TRIPOD: Treating insulin resistance reduces incidence of type 2 diabetesTRoglitazone In Prevention Of Diabetesn = 236 Hispanic women with gestational diabetes

60

40

20

0

New-onset diabetes

(%)

Follow-up (months)

0 12 24 36 48 60

Buchanan TA et al. Diabetes. 2002;51:2796-803.

Placebo

Troglitazone 400 mg

12.1%

5.4%

Annual incidence

55% RRRHR 0.45 (0.25–0.83)*

P = 0.009

*Unadjusted

0

TZDs blunt diabetes progression

DPP Research Group.Diabetes. 2005;54:1150-6.*Withdrawn from study after 1.5 yr

Diabetes Prevention Program

10

15

5

1.5

Cumulativeincidence

of diabetes(%)

Years

1.00.50

Placebo

Metformin850 mg bid

Lifestyle

Troglitazone400 mg/d*

23773915682343n =

75% vs placeboP < 0.001

Primary outcome:Diabetes or death from any cause

DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

DREAM: Study design

Secondary outcomes I: CV eventsCombined MI, stroke, CV death, revascularization, HF, angina,

ventricular arrhythmia

Secondary outcomes II: Renal eventsCombined microalbuminuria,

macroalbuminuria, or 30% in CrCl

Ramipril 15 mg/d + Rosiglitazone 8 mg/d

Ramipril 15 mg/d+ Placebo

Placebo+ Placebo

Rosiglitazone 8 mg/d+ Placebo

Randomized, double-blind 2 × 2 factorial designN = 5269 with IFG and/or IGT

Follow-up: 3–5 years

DREAM: 2 x 2 factorial design

DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

Rosiglitazone Placebo

RamiprilRamipril +

RosiglitazoneRamipril +Placebo

PlaceboRosiglitazone +

PlaceboPlacebo +Placebo

N = 5269 with IFG and/or IGT

DREAM: Inclusion criteria

• Age ≥30 years

• IFG and/or IGT – Fasting plasma glucose 100–125 mg/dL– 2-hour 75 g OGTT 140–199 mg/dL

DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

N = 5269

DREAM: Key exclusion criteria

• ACEI/TZD use or contraindication

• LVEF <40% or other CVD with ACEI indication

• Diabetes

• Renal disease, including renal artery stenosis

• Diseases/medications that affect glucose tolerance

• Use of steroids/niacin

• Pregnancy

DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

DREAM: Baseline characteristics

Age (years) 54.7

Women (%) 58.5

Women with prior gestational diabetes (%) 9.3

Hypertension (%) 43.5

Hyperlipidemia (%) 35.5

BP (mm Hg) 136/83

BMI (kg/m2) 30.5

Waist-hip ratio, men 0.96

Waist-hip ratio, women 0.87

Waist circumference, men (in) 34.3

Waist circumference, women (in) 32.6

DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

DREAM: Baseline glucose status

• Isolated IGT 1835 (35%)

• Isolated IFG* 739 (14%)

• IGT and IFG* 2692 (51%)

• FPG (mean) 104

• 2-hr plasma glucose (mean) 157

DREAM Trial Investigators. Diabetologia. 2004;47:1519-27. *Based on 100 mg/dL threshold

n

mg/dL

DREAM: Beyond diabetes prevention

IFG and IGT are strong risk factors for CV disease

• Does treatment with rosiglitazone and/or ramipril improve IFG, IGT, and glucose control?

• Positive result for either or both drugs will:

– Affirm that links between RAAS, glucose homeostasis, andCV disease are clinically important

– Highlight relevance of elevated glucose levels as modifiablerisk factors for CV disease

DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

DREAM: Substudies

STARR (STudy of Atherosclerosis with Ramipril and Rosiglitazone)(N = 1427)• Carotid atherosclerosis progression

DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

EpiDREAM: Epidemiologic follow-up of individuals screened butnot randomized for DREAM (N ≈ 20,000)• Environmental/genetic determinants of diabetes, obesity, and

CV disease

Effects of rampiril and rosiglitazone• Conversion of IGT to normal glucose tolerance• Insulin resistance and -cell function• FPG, 2-hr plasma glucose, A1C

ADOPT: Study objective

• What is the long-term efficacy of monotherapy with rosiglitazone vs metformin or glyburide on glucose control in patients with type 2 diabetes (diagnosed≤3 years)?

A Diabetes Outcome Progression Trial

Viberti G et al. Diabetes Care. 2002;25:1737-43.

ADOPT: Study design

Follow-up: 4 years

Viberti G et al. Diabetes Care. 2002;25:1737-43.

Glyburide 15 mg/day* Metformin 2 g/day*

Secondary outcomes: Changes in A1C, FPG, -cell function, insulin sensitivity, lipids, BP, albumin excretion, PAI-1, fibrinogen, CRP

Primary outcome:Time to monotherapy failure

Rosiglitazone 8 mg/day*

*Titrated to maximum tolerated dose

Randomized, double-blind, parallel group designN ≈ 3600, drug naïve with type 2 diabetes <3 years

CHICAGO: Study objective

• How effective is pioglitazone in controlling the progression of atherosclerosis in patients with type 2 diabetes, as measured by carotid artery thickness?

NIH. www.clinicaltrials.gov.Mazzone T. Am J Cardiol. 2004;93(suppl):27C-31C.

Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone trial

CHICAGO: Study design

*Titrated to reach glycemic controlNIH. www.clinicaltrials.gov.

Mazzone T. Am J Cardiol. 2004;93(suppl):27C-31C.

Double-blind, randomized, active control, parallel-efficacy study Type 2 diabetes, asymptomatic for CAD

N ≈ 462

Pioglitazone 15, 30, or 45 mg* Glimepiride 1, 2, or 4 mg*

Primary outcome: Change in carotid intima-media thickness at 18 months

Secondary outcome: Carotid artery calcium score